Adaptive endoplasmic reticulum stress signalling via IRE1α-XBP1 preserves self-renewal of haematopoietic and pre-leukaemic stem cells

Over their lifetime, long-term haematopoietic stem cells (HSC) are exposed to a variety of stress conditions that they must endure. Many stresses, such as infection/inflammation, reactive oxygen species, nutritional deprivation and hypoxia, activate unfolded protein response signalling, which induces either adaptive changes to resolve the stress or apoptosis to clear the damaged cell. Whether unfolded-protein-response signalling plays any role in HSC regulation remains to be established. Here, we report that the adaptive signalling of the unfolded protein response, IRE1 alpha-XBP1, protects HSCs from endoplasmic reticulum stress-induced apoptosis. IRE1 alpha knockout leads to reduced reconstitution of HSCs. Furthermore, we show that oncogenic N-Ras(G12D) activates IRE1 alpha-XBP1, through MEK-GSK3 beta, to promote HSC survival under endoplasmic reticulum stress. Inhibiting IRE1 alpha-XBP1 abolished N-Ras(G12D)-mediated survival under endoplasmic reticulum stress and diminished the competitive advantage of Nras(G12D) HSCs in transplant recipients. Our studies illuminate how the adaptive endoplasmic reticulum stress response is advantageous in sustaining self-renewal of HSCs and promoting pre-leukaemic clonal dominance.